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Pharmacogenetics of Drug Therapies in Rheumatoid Arthritis

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Pharmacogenomics in Drug Discovery and Development

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2547))

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Abstract

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder that can lead to severe joint damage and is often associated with a high morbidity and disability. Disease-modifying anti-rheumatic drugs (DMARDs) are the mainstay of treatment in RA. DMARDs not only relieve the clinical signs and symptoms of RA but also inhibit the radiographic progression of disease and reduce the effects of chronic systemic inflammation. Since the introduction of biologic DMARDs in the late 1990s, the therapeutic range of options for the management of RA has significantly expanded. However, patients’ response to these agents is not uniform with considerable variability in both efficacy and toxicity. There are no reliable means of predicting an individual patient’s response to a given DMARD prior to initiation of therapy. In this chapter, the current published literature on the pharmacogenetics of traditional DMARDS and the newer biologic DMARDs in RA is highlighted. Pharmacogenetics may help individualize drug therapy in patients with RA by providing reliable biomarkers to predict medication toxicity and efficacy.

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References

  1. Weinblatt ME, Coblyn JS, Fox DA et al (1985) Efficacy of low-dose methotrexate in rheumatoid arthritis. N Engl J Med 312(13):818–822

    Article  CAS  PubMed  Google Scholar 

  2. Bathon JM, Martin RW, Fleischmann RM et al (2000) A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 343(22):1586–1593

    Article  CAS  PubMed  Google Scholar 

  3. Bluett J, Sergeant JC, MacGregor AJ et al (2018) Risk factors for oral methotrexate failure in patients with inflammatory polyarthritis: results from a UK prospective cohort study. Arthritis Res Ther 20(1):50

    Article  PubMed  PubMed Central  Google Scholar 

  4. Hooijberg JH, Broxterman HJ, Kool M et al (1999) Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2. Cancer Res 59(11):2532–2535

    CAS  PubMed  Google Scholar 

  5. Barredo JC, Synold TW, Laver J et al (1994) Differences in constitutive and post-methotrexate folylpolyglutamate synthetase activity in B-lineage and T-lineage leukemia. Blood 84(2):564–569

    Article  CAS  PubMed  Google Scholar 

  6. Galivan J (1980) Evidence for the cytotoxic activity of polyglutamate derivatives of methotrexate. Mol Pharmacol 17(1):105–110

    CAS  PubMed  Google Scholar 

  7. Szeto DW, Cheng YC, Rosowsky A et al (1979) Human thymidylate synthetase--III. Effects of methotrexate and folate analogs. Biochem Pharmacol 28(17):2633–2637

    Article  CAS  PubMed  Google Scholar 

  8. Chan ES, Cronstein BN (2002) Molecular action of methotrexate in inflammatory diseases. Arthritis Res 4(4):266–273

    Article  PubMed  PubMed Central  Google Scholar 

  9. Rothem L, Aronheim A, Assaraf YG (2003) Alterations in the expression of transcription factors and the reduced folate carrier as a novel mechanism of antifolate resistance in human leukemia cells. J Biol Chem 278(11):8935–8941

    Article  CAS  PubMed  Google Scholar 

  10. Rothem L, Stark M, Kaufman Y et al (2004) Reduced folate carrier gene silencing in multiple antifolate-resistant tumor cell lines is due to a simultaneous loss of function of multiple transcription factors but not promoter methylation. J Biol Chem 279(1):374–384

    Article  CAS  PubMed  Google Scholar 

  11. Whetstine JR, Witt TL, Matherly LH (2002) The human reduced folate carrier gene is regulated by the AP2 and sp1 transcription factor families and a functional 61-base pair polymorphism. J Biol Chem 277(46):43873–43880

    Article  CAS  PubMed  Google Scholar 

  12. Dervieux T, Kremer J, Lein DO et al (2004) Contribution of common polymorphisms in reduced folate carrier and gamma-glutamylhydrolase to methotrexate polyglutamate levels in patients with rheumatoid arthritis. Pharmacogenetics 14(11):733–739

    Article  CAS  PubMed  Google Scholar 

  13. Hayashi H, Fujimaki C, Daimon T et al (2009) Genetic polymorphisms in folate pathway enzymes as a possible marker for predicting the outcome of methotrexate therapy in Japanese patients with rheumatoid arthritis. J Clin Pharm Ther 34(3):355–361

    Article  CAS  PubMed  Google Scholar 

  14. Hoffmeyer S, Burk O, von Richter O et al (2000) Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci U S A 97(7):3473–3478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kim RB, Leake BF, Choo EF et al (2001) Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther 70(2):189–199

    Article  CAS  PubMed  Google Scholar 

  16. Norris MD, De Graaf D, Haber M et al (1996) Involvement of MDR1 P-glycoprotein in multifactorial resistance to methotrexate. Int J Cancer 65(5):613–619

    Article  CAS  PubMed  Google Scholar 

  17. Mickisch GH, Merlino GT, Galski H et al (1991) Transgenic mice that express the human multidrug-resistance gene in bone marrow enable a rapid identification of agents that reverse drug resistance. Proc Natl Acad Sci U S A 88(2):547–551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Pawlik A, Wrzesniewska J, Fiedorowicz-Fabrycy I et al (2004) The MDR1 3435 polymorphism in patients with rheumatoid arthritis. Int J Clin Pharmacol Ther 42(9):496–503

    Article  CAS  PubMed  Google Scholar 

  19. Moya P, Salazar J, Arranz MJ et al (2016) Methotrexate pharmacokinetic genetic variants are associated with outcome in rheumatoid arthritis patients. Pharmacogenomics 17(1):25–29

    Article  PubMed  Google Scholar 

  20. Rozen R (1996) Molecular genetics of methylenetetrahydrofolate reductase deficiency. J Inherit Metab Dis 19(5):589–594

    Article  CAS  PubMed  Google Scholar 

  21. Frosst P, Blom HJ, Milos R et al (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10(1):111–113

    Article  CAS  PubMed  Google Scholar 

  22. van der Put NM, Gabreels F, Stevens EM et al (1998) A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet 62(5):1044–1051

    Article  PubMed  PubMed Central  Google Scholar 

  23. Kang SS, Zhou J, Wong PW et al (1988) Intermediate homocysteinemia: a thermolabile variant of methylenetetrahydrofolate reductase. Am J Hum Genet 43(4):414–421

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Haagsma CJ, Blom HJ, van Riel PL et al (1999) Influence of sulphasalazine, methotrexate, and the combination of both on plasma homocysteine concentrations in patients with rheumatoid arthritis. Ann Rheum Dis 58(2):79–84

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. van Ede AE, Laan RF, Blom HJ et al (2001) The C677T mutation in the methylenetetrahydrofolate reductase gene: a genetic risk factor for methotrexate-related elevation of liver enzymes in rheumatoid arthritis patients. Arthritis Rheum 44(11):2525–2530

    Article  PubMed  Google Scholar 

  26. Berkun Y, Levartovsky D, Rubinow A et al (2004) Methotrexate related adverse effects in patients with rheumatoid arthritis are associated with the A1298C polymorphism of the MTHFR gene. Ann Rheum Dis 63(10):1227–1231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Dervieux T, Greenstein N, Kremer J (2006) Pharmacogenomic and metabolic biomarkers in the folate pathway and their association with methotrexate effects during dosage escalation in rheumatoid arthritis. Arthritis Rheum 54(10):3095–3103

    Article  CAS  PubMed  Google Scholar 

  28. Kurzawski M, Pawlik A, Safranow K et al (2007) 677C>T and 1298A>C MTHFR polymorphisms affect methotrexate treatment outcome in rheumatoid arthritis. Pharmacogenomics 8(11):1551–1559

    Article  CAS  PubMed  Google Scholar 

  29. Wessels JA, de Vries-Bouwstra JK, Heijmans BT et al (2006) Efficacy and toxicity of methotrexate in early rheumatoid arthritis are associated with single-nucleotide polymorphisms in genes coding for folate pathway enzymes. Arthritis Rheum 54(4):1087–1095

    Article  CAS  PubMed  Google Scholar 

  30. Taniguchi A, Urano W, Tanaka E et al (2007) Validation of the associations between single nucleotide polymorphisms or haplotypes and responses to disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: a proposal for prospective pharmacogenomic study in clinical practice. Pharmacogenet Genomics 17(6):383–390

    Article  CAS  PubMed  Google Scholar 

  31. Kim SK, Jun JB, El-Sohemy A et al (2006) Cost-effectiveness analysis of MTHFR polymorphism screening by polymerase chain reaction in Korean patients with rheumatoid arthritis receiving methotrexate. J Rheumatol 33(7):1266–1274

    CAS  PubMed  Google Scholar 

  32. Xiao H, Xu J, Zhou X et al (2010) Associations between the genetic polymorphisms of MTHFR and outcomes of methotrexate treatment in rheumatoid arthritis. Clin Exp Rheumatol 28(5):728–733

    CAS  PubMed  Google Scholar 

  33. Weisman MH, Furst DE, Park GS et al (2006) Risk genotypes in folate-dependent enzymes and their association with methotrexate-related side effects in rheumatoid arthritis. Arthritis Rheum 54(2):607–612

    Article  CAS  PubMed  Google Scholar 

  34. Ranganathan P, Culverhouse R, Marsh S et al (2008) Methotrexate (MTX) pathway gene polymorphisms and their effects on MTX toxicity in Caucasian and African American patients with rheumatoid arthritis. J Rheumatol 35(4):572–579

    CAS  PubMed  Google Scholar 

  35. Caliz R, del Amo J, Balsa A et al (2012) The C677T polymorphism in the MTHFR gene is associated with the toxicity of methotrexate in a Spanish rheumatoid arthritis population. Scand J Rheumatol 41(1):10–14

    Article  CAS  PubMed  Google Scholar 

  36. Fisher MC, Cronstein BN (2009) Metaanalysis of methylenetetrahydrofolate reductase (MTHFR) polymorphisms affecting methotrexate toxicity. J Rheumatol 36(3):539–545

    Article  PubMed  PubMed Central  Google Scholar 

  37. Lee YH, Song GG (2010) Associations between the C677T and A1298C polymorphisms of MTHFR and the efficacy and toxicity of methotrexate in rheumatoid arthritis: a meta-analysis. Clin Drug Investig 30(2):101–108

    Article  CAS  PubMed  Google Scholar 

  38. Owen SA, Lunt M, Bowes J et al (2013) MTHFR gene polymorphisms and outcome of methotrexate treatment in patients with rheumatoid arthritis: analysis of key polymorphisms and meta-analysis of C677T and A1298C polymorphisms. Pharmacogenomics J 13(2):137–147

    Article  CAS  PubMed  Google Scholar 

  39. Horie N, Aiba H, Oguro K et al (1995) Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5′-terminal regulatory region of the human gene for thymidylate synthase. Cell Struct Funct 20(3):191–197

    Article  CAS  PubMed  Google Scholar 

  40. Kawakami K, Omura K, Kanehira E et al (1999) Polymorphic tandem repeats in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers. Anticancer Res 19(4B):3249–3252

    CAS  PubMed  Google Scholar 

  41. DiPaolo A, Chu E (2004) The role of thymidylate synthase as a molecular biomarker. Clin Cancer Res 10(2):411–412

    Article  CAS  PubMed  Google Scholar 

  42. Pullarkat ST, Stoehlmacher J, Ghaderi V et al (2001) Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J 1(1):65–70

    Article  CAS  PubMed  Google Scholar 

  43. Kawakami K, Watanabe G (2003) Identification and functional analysis of single nucleotide polymorphism in the tandem repeat sequence of thymidylate synthase gene. Cancer Res 63(18):6004–6007

    CAS  PubMed  Google Scholar 

  44. Ulrich CM, Bigler J, Velicer CM et al (2000) Searching expressed sequence tag databases: discovery and confirmation of a common polymorphism in the thymidylate synthase gene. Cancer Epidemiol Biomark Prev 9(12):1381–1385

    CAS  Google Scholar 

  45. Kumagai K, Hiyama K, Oyama T et al (2003) Polymorphisms in the thymidylate synthase and methylenetetrahydrofolate reductase genes and sensitivity to the low-dose methotrexate therapy in patients with rheumatoid arthritis. Int J Mol Med 11(5):593–600

    CAS  PubMed  Google Scholar 

  46. Lv S, Fan H, Li J et al (2018) Genetic polymorphisms of TYMS, MTHFR, ATIC, MTR, and MTRR are related to the outcome of methotrexate therapy for rheumatoid arthritis in a Chinese population. Front Pharmacol 9:1390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sherr CJ (1994) G1 phase progression: cycling on cue. Cell 79(4):551–555

    Article  CAS  PubMed  Google Scholar 

  48. Betticher DC, Thatcher N, Altermatt HJ et al (1995) Alternate splicing produces a novel cyclin D1 transcript. Oncogene 11(5):1005–1011

    CAS  PubMed  Google Scholar 

  49. Lu F, Gladden AB, Diehl JA (2003) An alternatively spliced cyclin D1 isoform, cyclin D1b, is a nuclear oncogene. Cancer Res 63(21):7056–7061

    CAS  PubMed  Google Scholar 

  50. Hochhauser D, Schnieders B, Ercikan-Abali E et al (1996) Effect of cyclin D1 overexpression on drug sensitivity in a human fibrosarcoma cell line. J Natl Cancer Inst 88(18):1269–1275

    Article  CAS  PubMed  Google Scholar 

  51. Jekic B, Lukovic L, Bunjevacki V et al (2013) Association of the TYMS 3G/3G genotype with poor response and GGH 354GG genotype with the bone marrow toxicity of the methotrexate in RA patients. Eur J Clin Pharmacol 69(3):377–383

    Article  CAS  PubMed  Google Scholar 

  52. Dervieux T, Furst D, Lein DO et al (2004) Polyglutamation of methotrexate with common polymorphisms in reduced folate carrier, aminoimidazole carboxamide ribonucleotide transformylase, and thymidylate synthase are associated with methotrexate effects in rheumatoid arthritis. Arthritis Rheum 50(9):2766–2774

    Article  CAS  PubMed  Google Scholar 

  53. Grabar PB, Rojko S, Logar D et al (2010) Genetic determinants of methotrexate treatment in rheumatoid arthritis patients: a study of polymorphisms in the adenosine pathway. Ann Rheum Dis 69(5):931–932

    Article  CAS  PubMed  Google Scholar 

  54. Wessels JA, van der Kooij SM, le Cessie S et al (2007) A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent-onset rheumatoid arthritis. Arthritis Rheum 56(6):1765–1775

    Article  CAS  PubMed  Google Scholar 

  55. Lopez-Rodriguez R, Ferreiro-Iglesias A, Lima A et al (2018) Evaluation of a clinical pharmacogenetics model to predict methotrexate response in patients with rheumatoid arthritis. Pharmacogenomics J 18(4):539–545

    Article  CAS  PubMed  Google Scholar 

  56. Stolk JN, Boerbooms AM, de Abreu RA et al (1998) Reduced thiopurine methyltransferase activity and development of side effects of azathioprine treatment in patients with rheumatoid arthritis. Arthritis Rheum 41(10):1858–1866

    Article  CAS  PubMed  Google Scholar 

  57. Marinaki AM, Ansari A, Duley JA et al (2004) Adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase). Pharmacogenetics 14(3):181–187

    Article  CAS  PubMed  Google Scholar 

  58. Haglund S, Taipalensuu J, Peterson C et al (2008) IMPDH activity in thiopurine-treated patients with inflammatory bowel disease - relation to TPMT activity and metabolite concentrations. Br J Clin Pharmacol 65(1):69–77

    Article  CAS  PubMed  Google Scholar 

  59. Haglund S, Vikingsson S, Soderman J et al (2011) The role of inosine-5′-monophosphate dehydrogenase in thiopurine metabolism in patients with inflammatory bowel disease. Ther Drug Monit 33(2):200–208

    Article  CAS  PubMed  Google Scholar 

  60. Citterio-Quentin A, El Mahmoudi A, Perret T, at al. (2019) Red blood cell IMPDH activity in adults and children with or without azathioprine: relationship between thiopurine metabolites, ITPA and TPMT activities. Basic Clin Pharmacol Toxicol 124(5):600–606

    Article  CAS  PubMed  Google Scholar 

  61. Krynetski EY, Tai HL, Yates CR et al (1996) Genetic polymorphism of thiopurine S-methyltransferase: clinical importance and molecular mechanisms. Pharmacogenetics 6(4):279–290

    Article  CAS  PubMed  Google Scholar 

  62. Tai HL, Krynetski EY, Yates CR et al (1996) Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. Am J Hum Genet 58(4):694–702

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Tai HL, Krynetski EY, Schuetz EG et al (1997) Enhanced proteolysis of thiopurine S-methyltransferase (TPMT) encoded by mutant alleles in humans (TPMT*3A, TPMT*2): mechanisms for the genetic polymorphism of TPMT activity. Proc Natl Acad Sci U S A 94(12):6444–6449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Yates CR, Krynetski EY, Loennechen T et al (1997) Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med 126(8):608–614

    Article  CAS  PubMed  Google Scholar 

  65. Ameyaw MM, Collie-Duguid ES, Powrie RH et al (1999) Thiopurine methyltransferase alleles in British and Ghanaian populations. Hum Mol Genet 8(2):367–370

    Article  CAS  PubMed  Google Scholar 

  66. Hon YY, Fessing MY, Pui CH et al (1999) Polymorphism of the thiopurine S-methyltransferase gene in African-Americans. Hum Mol Genet 8(2):371–376

    Article  CAS  PubMed  Google Scholar 

  67. Evans WE, Hon YY, Bomgaars L et al (2001) Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J Clin Oncol 19(8):2293–2301

    Article  CAS  PubMed  Google Scholar 

  68. Black AJ, McLeod HL, Capell HA et al (1998) Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine. Ann Intern Med 129(9):716–718

    Article  CAS  PubMed  Google Scholar 

  69. Corominas H, Domenech M, Laiz A et al (2003) Is thiopurine methyltransferase genetic polymorphism a major factor for withdrawal of azathioprine in rheumatoid arthritis patients? Rheumatology (Oxford) 42(1):40–45

    Article  CAS  PubMed  Google Scholar 

  70. Boonsrirat U, Angsuthum S, Vannaprasaht S et al (2008) Azathioprine-induced fatal myelosuppression in systemic lupus erythematosus patient carrying TPMT*3C polymorphism. Lupus 17(2):132–134

    Article  CAS  PubMed  Google Scholar 

  71. Higgs JE, Payne K, Roberts C et al (2010) Are patients with intermediate TPMT activity at increased risk of myelosuppression when taking thiopurine medications? Pharmacogenomics 11(2):177–188

    Article  CAS  PubMed  Google Scholar 

  72. von Ahsen N, Armstrong VW, Behrens C et al (2005) Association of inosine triphosphatase 94C>A and thiopurine S-methyltransferase deficiency with adverse events and study drop-outs under azathioprine therapy in a prospective Crohn disease study. Clin Chem 51(12):2282–2288

    Article  Google Scholar 

  73. Shipkova M, Franz J, Abe M et al (2011) Association between adverse effects under azathioprine therapy and inosine triphosphate pyrophosphatase activity in patients with chronic inflammatory bowel disease. Ther Drug Monit 33(3):321–328

    Article  CAS  PubMed  Google Scholar 

  74. Gearry RB, Roberts RL, Barclay ML et al (2004) Lack of association between the ITPA 94C>A polymorphism and adverse effects from azathioprine. Pharmacogenetics 14(11):779–781

    Article  CAS  PubMed  Google Scholar 

  75. Eklund BI, Moberg M, Bergquist J et al (2006) Divergent activities of human glutathione transferases in the bioactivation of azathioprine. Mol Pharmacol 70(2):747–754

    Article  CAS  PubMed  Google Scholar 

  76. Stocco G, Martelossi S, Barabino A et al (2007) Glutathione-S-transferase genotypes and the adverse effects of azathioprine in young patients with inflammatory bowel disease. Inflamm Bowel Dis 13(1):57–64

    Article  PubMed  Google Scholar 

  77. Stocco G, Cuzzoni E, De Iudicibus S et al (2014) Deletion of glutathione-s-transferase m1 reduces azathioprine metabolite concentrations in young patients with inflammatory bowel disease. J Clin Gastroenterol 48(1):43–51

    Article  CAS  PubMed  Google Scholar 

  78. Kerstens PJ, Stolk JN, De Abreu RA et al (1995) Azathioprine-related bone marrow toxicity and low activities of purine enzymes in patients with rheumatoid arthritis. Arthritis Rheum 38(1):142–145

    Article  CAS  PubMed  Google Scholar 

  79. Yang J, Wang P, Qin Z et al (2019) NUDT15 and TPMT genetic polymorphisms are related to azathioprine intolerance in Chinese patients with rheumatic diseases. Genet Test Mol Biomarkers 23(10):751–757

    Article  CAS  PubMed  Google Scholar 

  80. Relling MV, Schwab M, Whirl-Carrillo M et al (2019) Clinical Pharmacogenetics implementation consortium guideline for thiopurine dosing based on TPMT and NUDT15 genotypes: 2018 update. Clin Pharmacol Ther 105(5):1095–1105

    Article  CAS  PubMed  Google Scholar 

  81. Das KM, Eastwood MA, McManus JP et al (1973) Adverse reactions during salicylazosulfapyridine therapy and the relation with drug metabolism and acetylator phenotype. N Engl J Med 289(10):491–495

    Article  CAS  PubMed  Google Scholar 

  82. Pullar T, Capell HA (2006) Variables affecting efficacy and toxicity of sulphasalazine in rheumatoid arthritis. A review. Drugs 32(Suppl 1):54–57

    Google Scholar 

  83. Zaher H, Khan AA, Palandra J et al (2006) Breast cancer resistance protein (Bcrp/abcg2) is a major determinant of sulfasalazine absorption and elimination in the mouse. Mol Pharm 3(1):55–61

    Article  CAS  PubMed  Google Scholar 

  84. Yamasaki Y, Ieiri I, Kusuhara H et al (2008) Pharmacogenetic characterization of sulfasalazine disposition based on NAT2 and ABCG2 (BCRP) gene polymorphisms in humans. Clin Pharmacol Ther 84(1):95–103

    Article  CAS  PubMed  Google Scholar 

  85. Wiese MD, Alotaibi N, O'Doherty C et al (2014) Pharmacogenomics of NAT2 and ABCG2 influence the toxicity and efficacy of sulphasalazine containing DMARD regimens in early rheumatoid arthritis. Pharmacogenomics J 14(4):350–355

    Article  CAS  PubMed  Google Scholar 

  86. Tanaka E, Taniguchi A, Urano W et al (2002) Adverse effects of sulfasalazine in patients with rheumatoid arthritis are associated with diplotype configuration at the N-acetyltransferase 2 gene. J Rheumatol 29(12):2492–2499

    CAS  PubMed  Google Scholar 

  87. Wadelius M, Stjernberg E, Wiholm BE et al (2000) Polymorphisms of NAT2 in relation to sulphasalazine-induced agranulocytosis. Pharmacogenetics 10(1):35–41

    Article  CAS  PubMed  Google Scholar 

  88. Kuhn UD, Anschutz M, Schmucker K et al (2010) Phenotyping with sulfasalazine - time dependence and relation to NAT2 pharmacogenetics. Int J Clin Pharmacol Ther 48(1):1–10

    Article  CAS  PubMed  Google Scholar 

  89. Yee J, Kim SM, Han JM et al (2020) The association between NAT2 acetylator status and adverse drug reactions of sulfasalazine: a systematic review and meta-analysis. Sci Rep 10(1):3658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Genovese MC, Bathon JM, Martin RW et al (2002) Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes. Arthritis Rheum 46(6):1443–1450

    Article  CAS  PubMed  Google Scholar 

  91. Maini RN, Breedveld FC, Kalden JR et al (1998) Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 41(9):1552–1563

    Article  CAS  PubMed  Google Scholar 

  92. Keystone EC, Kavanaugh AF, Sharp JT et al (2004) Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum 50(5):1400–1411

    Article  CAS  PubMed  Google Scholar 

  93. Seitz M, Wirthmuller U, Moller B et al (2007) The −308 tumour necrosis factor-alpha gene polymorphism predicts therapeutic response to TNFalpha-blockers in rheumatoid arthritis and spondyloarthritis patients. Rheumatology (Oxford) 46(1):93–96

    Article  CAS  PubMed  Google Scholar 

  94. Cuchacovich M, Ferreira L, Aliste M et al (2004) Tumour necrosis factor-alpha (TNF-alpha) levels and influence of −308 TNF-alpha promoter polymorphism on the responsiveness to infliximab in patients with rheumatoid arthritis. Scand J Rheumatol 33(4):228–232

    Article  CAS  PubMed  Google Scholar 

  95. Pavy S, Toonen EJ, Miceli-Richard C et al (2010) Tumour necrosis factor alpha −308G->A polymorphism is not associated with response to TNFalpha blockers in Caucasian patients with rheumatoid arthritis: systematic review and meta-analysis. Ann Rheum Dis 69(6):1022–1028

    Article  CAS  PubMed  Google Scholar 

  96. Zeng Z, Duan Z, Zhang T et al (2013) Association between tumor necrosis factor-alpha (TNF-alpha) promoter −308 G/A and response to TNF-alpha blockers in rheumatoid arthritis: a meta-analysis. Mod Rheumatol 23(3):489–495

    Article  CAS  PubMed  Google Scholar 

  97. Maxwell JR, Potter C, Hyrich KL et al (2008) Association of the tumour necrosis factor-308 variant with differential response to anti-TNF agents in the treatment of rheumatoid arthritis. Hum Mol Genet 17(22):3532–3538

    Article  CAS  PubMed  Google Scholar 

  98. Fabris M, Di Poi E, D'Elia A et al (2002) Tumor necrosis factor-alpha gene polymorphism in severe and mild-moderate rheumatoid arthritis. J Rheumatol 29(1):29–33

    CAS  PubMed  Google Scholar 

  99. Morita C, Horiuchi T, Tsukamoto H et al (2001) Association of tumor necrosis factor receptor type II polymorphism 196R with systemic lupus erythematosus in the Japanese: molecular and functional analysis. Arthritis Rheum 44(12):2819–2827

    Article  CAS  PubMed  Google Scholar 

  100. Ongaro A, De Mattei M, Pellati A et al (2008) Can tumor necrosis factor receptor II gene 676T>G polymorphism predict the response grading to anti-TNFalpha therapy in rheumatoid arthritis? Rheumatol Int 28(9):901–908

    Article  CAS  PubMed  Google Scholar 

  101. Vasilopoulos Y, Bagiatis V, Stamatopoulou D et al (2011) Association of anti-CCP positivity and carriage of TNFRII susceptibility variant with anti-TNF-alpha response in rheumatoid arthritis. Clin Exp Rheumatol 29(4):701–704

    CAS  PubMed  Google Scholar 

  102. Criswell LA, Lum RF, Turner KN et al (2004) The influence of genetic variation in the HLA-DRB1 and LTA-TNF regions on the response to treatment of early rheumatoid arthritis with methotrexate or etanercept. Arthritis Rheum 50(9):2750–2756

    Article  CAS  PubMed  Google Scholar 

  103. Gregersen PK, Silver J, Winchester RJ (1987) The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum 30(11):1205–1213

    Article  CAS  PubMed  Google Scholar 

  104. Waldron-Lynch F, Adams C, Amos C et al (2001) Tumour necrosis factor 5′ promoter single nucleotide polymorphisms influence susceptibility to rheumatoid arthritis (RA) in immunogenetically defined multiplex RA families. Genes Immun 2(2):82–87

    Article  CAS  PubMed  Google Scholar 

  105. Mulcahy B, Waldron-Lynch F, McDermott MF et al (1996) Genetic variability in the tumor necrosis factor-lymphotoxin region influences susceptibility to rheumatoid arthritis. Am J Hum Genet 59(3):676–683

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Martinez A, Salido M, Bonilla G et al (2004) Association of the major histocompatibility complex with response to infliximab therapy in rheumatoid arthritis patients. Arthritis Rheum 50(4):1077–1082

    Article  CAS  PubMed  Google Scholar 

  107. Stahl EA, Raychaudhuri S, Remmers EF et al (2010) Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet 42(6):508–514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Cui J, Saevarsdottir S, Thomson B et al (2010) Rheumatoid arthritis risk allele PTPRC is also associated with response to anti-tumor necrosis factor alpha therapy. Arthritis Rheum 62(7):1849–1861

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Plant D, Prajapati R, Hyrich KL et al (2012) Replication of association of the PTPRC gene with response to anti-tumor necrosis factor therapy in a large UK cohort. Arthritis Rheum 64(3):665–670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Krintel SB, Palermo G, Johansen JS et al (2012) Investigation of single nucleotide polymorphisms and biological pathways associated with response to TNFalpha inhibitors in patients with rheumatoid arthritis. Pharmacogenet Genomics 22(8):577–589

    Article  CAS  PubMed  Google Scholar 

  111. Bowes JD, Potter C, Gibbons LJ et al (2009) Investigation of genetic variants within candidate genes of the TNFRSF1B signalling pathway on the response to anti-TNF agents in a UK cohort of rheumatoid arthritis patients. Pharmacogenet Genomics 19(4):319–323

    Article  CAS  PubMed  Google Scholar 

  112. Coulthard LR, Taylor JC, Eyre S et al (2011) Genetic variants within the MAP kinase signalling network and anti-TNF treatment response in rheumatoid arthritis patients. Ann Rheum Dis 70(1):98–103

    Article  PubMed  Google Scholar 

  113. Barton A, Eyre S, Ke X et al (2009) Identification of AF4/FMR2 family, member 3 (AFF3) as a novel rheumatoid arthritis susceptibility locus and confirmation of two further pan-autoimmune susceptibility genes. Hum Mol Genet 18(13):2518–2522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Hafler JP, Maier LM, Cooper JD et al (2009) CD226 Gly307Ser association with multiple autoimmune diseases. Genes Immun 10(1):5–10

    Article  CAS  PubMed  Google Scholar 

  115. Tan RJ, Gibbons LJ, Potter C et al (2010) Investigation of rheumatoid arthritis susceptibility genes identifies association of AFF3 and CD226 variants with response to anti-tumour necrosis factor treatment. Ann Rheum Dis 69(6):1029–1035

    Article  CAS  PubMed  Google Scholar 

  116. Conigliaro P, Ciccacci C, Politi C et al (2017) Polymorphisms in STAT4, PTPN2, PSORS1C1 and TRAF3IP2 genes are associated with the response to TNF inhibitors in patients with rheumatoid arthritis. PLoS One 12(1):e0169956

    Article  PubMed  PubMed Central  Google Scholar 

  117. Marotte H, Pallot-Prades B, Grange L et al (2006) The shared epitope is a marker of severity associated with selection for, but not with response to, infliximab in a large rheumatoid arthritis population. Ann Rheum Dis 65(3):342–347

    Article  CAS  PubMed  Google Scholar 

  118. Padyukov L, Lampa J, Heimburger M et al (2003) Genetic markers for the efficacy of tumour necrosis factor blocking therapy in rheumatoid arthritis. Ann Rheum Dis 62(6):526–529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Schotte H, Schluter B, Drynda S et al (2005) Interleukin 10 promoter microsatellite polymorphisms are associated with response to long term treatment with etanercept in patients with rheumatoid arthritis. Ann Rheum Dis 64(4):575–581

    Article  CAS  PubMed  Google Scholar 

  120. Jancic I, Arsenovic-Ranin N, Sefik-Bukilica M et al (2013) 174G/C interleukin-6 gene promoter polymorphism predicts therapeutic response to etanercept in rheumatoid arthritis. Rheumatol Int 33(6):1481–1486

    Article  CAS  PubMed  Google Scholar 

  121. Sode J, Vogel U, Bank S et al (2014) Anti-TNF treatment response in rheumatoid arthritis patients is associated with genetic variation in the NLRP3-inflammasome. PLoS One 9(6):e100361

    Article  PubMed  PubMed Central  Google Scholar 

  122. Sode J, Vogel U, Bank S et al (2015) Genetic variations in pattern recognition receptor loci are associated with anti-TNF response in patients with rheumatoid arthritis. PLoS One 10(10):e0139781

    Article  PubMed  PubMed Central  Google Scholar 

  123. Potter C, Cordell HJ, Barton A et al (2010) Association between anti-tumour necrosis factor treatment response and genetic variants within the TLR and NF{kappa}B signalling pathways. Ann Rheum Dis 69(7):1315–1320

    Article  CAS  PubMed  Google Scholar 

  124. Sode J, Vogel U, Bank S et al (2018) Confirmation of an IRAK3 polymorphism as a genetic marker predicting response to anti-TNF treatment in rheumatoid arthritis. Pharmacogenomics J 18(1):81–86

    Article  CAS  PubMed  Google Scholar 

  125. Iwaszko M, Wielinska J, Swierkot J et al (2021) IL-33 gene polymorphisms as potential biomarkers of disease susceptibility and response to TNF inhibitors in rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis patients. Front Immunol 12:631603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Tutuncu Z, Kavanaugh A, Zvaifler N et al (2005) Fcgamma receptor type IIIA polymorphisms influence treatment outcomes in patients with inflammatory arthritis treated with tumor necrosis factor alpha-blocking agents. Arthritis Rheum 52(9):2693–2696

    Article  CAS  PubMed  Google Scholar 

  127. Canete JD, Suarez B, Hernandez MV et al (2009) Influence of variants of Fc gamma receptors IIA and IIIA on the American College of Rheumatology and European League Against Rheumatism responses to anti-tumour necrosis factor alpha therapy in rheumatoid arthritis. Ann Rheum Dis 68(10):1547–1552

    Article  CAS  PubMed  Google Scholar 

  128. Tsukahara S, Ikari K, Sato E et al (2008) A polymorphism in the gene encoding the Fcgamma IIIA receptor is a possible genetic marker to predict the primary response to infliximab in Japanese patients with rheumatoid arthritis. Ann Rheum Dis 67(12):1791–1792

    Article  CAS  PubMed  Google Scholar 

  129. Kastbom A, Bratt J, Ernestam S et al (2007) Fcgamma receptor type IIIA genotype and response to tumor necrosis factor alpha-blocking agents in patients with rheumatoid arthritis. Arthritis Rheum 56(2):448–452

    Article  CAS  PubMed  Google Scholar 

  130. Liu C, Batliwalla F, Li W et al (2008) Genome-wide association scan identifies candidate polymorphisms associated with differential response to anti-TNF treatment in rheumatoid arthritis. Mol Med 14(9–10):575–581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Umicevic Mirkov M, Cui J, Vermeulen SH et al (2013) Genome-wide association analysis of anti-TNF drug response in patients with rheumatoid arthritis. Ann Rheum Dis 72(8):1375–1381

    Article  PubMed  Google Scholar 

  132. Martin M, Romero X, de la Fuente MA et al (2001) CD84 functions as a homophilic adhesion molecule and enhances IFN-gamma secretion: adhesion is mediated by Ig-like domain 1. J Immunol 167(7):3668–3676

    Article  CAS  PubMed  Google Scholar 

  133. Tangye SG, Nichols KE, Hare NJ et al (2003) Functional requirements for interactions between CD84 and Src homology 2 domain-containing proteins and their contribution to human T cell activation. J Immunol 171(5):2485–2495

    Article  CAS  PubMed  Google Scholar 

  134. Cui J, Stahl EA, Saevarsdottir S et al (2013) Genome-wide association study and gene expression analysis identifies CD84 as a predictor of response to etanercept therapy in rheumatoid arthritis. PLoS Genet 9(3):e1003394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Acosta-Colman I, Palau N, Tornero J et al (2013) GWAS replication study confirms the association of PDE3A-SLCO1C1 with anti-TNF therapy response in rheumatoid arthritis. Pharmacogenomics 14(7):727–734

    Article  CAS  PubMed  Google Scholar 

  136. Honne K, Hallgrimsdottir I, Wu C et al (2016) A longitudinal genome-wide association study of anti-tumor necrosis factor response among Japanese patients with rheumatoid arthritis. Arthritis Res Ther 18:12

    Article  PubMed  PubMed Central  Google Scholar 

  137. Ferreiro-Iglesias A, Montes A, Perez-Pampin E et al (2019) Evaluation of 12 GWAS-drawn SNPs as biomarkers of rheumatoid arthritis response to TNF inhibitors. A potential SNP association with response to etanercept. PLoS One 14(2):e0213073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Bek S, Bojesen AB, Nielsen JV et al (2017) Systematic review and meta-analysis: pharmacogenetics of anti-TNF treatment response in rheumatoid arthritis. Pharmacogenomics J 17(5):403–411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Hensor EMA, McKeigue P, Ling SF et al (2019) Validity of a two-component imaging-derived disease activity score for improved assessment of synovitis in early rheumatoid arthritis. Rheumatology (Oxford) 58(8):1400–1409

    Article  PubMed  Google Scholar 

  140. Gilani SS, Nair N, Plant D et al (2020) Pharmacogenetics of TNF inhibitor response in rheumatoid arthritis utilizing the two-component disease activity score. Pharmacogenomics 21(16):1151–1156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Guan Y, Zhang H, Quang D et al (2019) Machine learning to predict anti-tumor necrosis factor drug responses of rheumatoid arthritis patients by integrating clinical and genetic markers. Arthritis Rheumatol 71(12):1987–1996

    Article  CAS  PubMed  Google Scholar 

  142. Daien CI, Fabre S, Rittore C et al (2012) TGF beta1 polymorphisms are candidate predictors of the clinical response to rituximab in rheumatoid arthritis. Joint Bone Spine 79(5):471–475

    Article  CAS  PubMed  Google Scholar 

  143. Coenen MJ, Gregersen PK (2009) Rheumatoid arthritis: a view of the current genetic landscape. Genes Immun 10(2):101–111

    Article  CAS  PubMed  Google Scholar 

  144. Boissier MC (2011) Cell and cytokine imbalances in rheumatoid synovitis. Joint Bone Spine 78(3):230–234

    Article  CAS  PubMed  Google Scholar 

  145. Guo Z, Binswanger U, Knoflach A (2002) Role of codon 10 and codon 25 polymorphisms on TGF-beta 1 gene expression and protein synthesis in stable renal allograft recipients. Transplant Proc 34(7):2904–2906

    Article  CAS  PubMed  Google Scholar 

  146. Ruyssen-Witrand A, Rouanet S, Combe B et al (2013) Association between -871C>T promoter polymorphism in the B-cell activating factor gene and the response to rituximab in rheumatoid arthritis patients. Rheumatology (Oxford) 52(4):636–641

    Article  CAS  PubMed  Google Scholar 

  147. Fabris M, Quartuccio L, Vital E et al (2013) The TTTT B lymphocyte stimulator promoter haplotype is associated with good response to rituximab therapy in seropositive rheumatoid arthritis resistant to tumor necrosis factor blockers. Arthritis Rheum 65(1):88–97

    Article  CAS  PubMed  Google Scholar 

  148. Ruyssen-Witrand A, Rouanet S, Combe B et al (2012) Fcgamma receptor type IIIA polymorphism influences treatment outcomes in patients with rheumatoid arthritis treated with rituximab. Ann Rheum Dis 71(6):875–877

    Article  CAS  PubMed  Google Scholar 

  149. Quartuccio L, Fabris M, Pontarini E et al (2014) The 158VV Fcgamma receptor 3A genotype is associated with response to rituximab in rheumatoid arthritis: results of an Italian multicentre study. Ann Rheum Dis 73(4):716–721

    Article  CAS  PubMed  Google Scholar 

  150. Kastbom A, Coster L, Arlestig L et al (2012) Influence of FCGR3A genotype on the therapeutic response to rituximab in rheumatoid arthritis: an observational cohort study. BMJ Open 2(5):e001524

    Article  PubMed  PubMed Central  Google Scholar 

  151. Sarsour K, Greenberg J, Johnston JA et al (2013) The role of the FcGRIIIa polymorphism in modifying the association between treatment and outcome in patients with rheumatoid arthritis treated with rituximab versus TNF-alpha antagonist therapies. Clin Exp Rheumatol 31(2):189–194

    PubMed  Google Scholar 

  152. Pal I, Szamosi S, Hodosi K et al (2017) Effect of Fcgamma-receptor 3a (FCGR3A) gene polymorphisms on rituximab therapy in Hungarian patients with rheumatoid arthritis. RMD Open 3(2):e000485

    Article  PubMed  PubMed Central  Google Scholar 

  153. Fabris M, Quartuccio L, Lombardi S et al (2012) The CC homozygosis of the -174G>C IL-6 polymorphism predicts a lower efficacy of rituximab therapy in rheumatoid arthritis. Autoimmun Rev 11(5):315–320

    Article  CAS  PubMed  Google Scholar 

  154. Vosslamber S, Raterman HG, van der Pouw Kraan TC et al (2011) Pharmacological induction of interferon type I activity following treatment with rituximab determines clinical response in rheumatoid arthritis. Ann Rheum Dis 70(6):1153–1159

    Article  CAS  PubMed  Google Scholar 

  155. Juge PA, Gazal S, Constantin A et al (2017) Variants of genes implicated in type 1 interferon pathway and B-cell activation modulate the EULAR response to rituximab at 24 weeks in rheumatoid arthritis. RMD Open 3(2):e000448

    Article  PubMed  PubMed Central  Google Scholar 

  156. Juge PA, van Steenbergen HW, Constantin A et al (2014) SPP1 rs9138 variant contributes to the severity of radiological damage in anti-citrullinated protein autoantibody-negative rheumatoid arthritis. Ann Rheum Dis 73(10):1840–1843

    Article  PubMed  Google Scholar 

  157. Wang J, Bansal AT, Martin M et al (2013) Genome-wide association analysis implicates the involvement of eight loci with response to tocilizumab for the treatment of rheumatoid arthritis. Pharmacogenomics J 13(3):235–241

    Article  PubMed  Google Scholar 

  158. Enevold C, Baslund B, Linde L et al (2014) Interleukin-6-receptor polymorphisms rs12083537, rs2228145, and rs4329505 as predictors of response to tocilizumab in rheumatoid arthritis. Pharmacogenet Genomics 24(8):401–405

    Article  CAS  PubMed  Google Scholar 

  159. Liu X, Xu J, Hu CD et al (2014) The relationship between SNPs in the genes of TLR signal transduction pathway downstream elements and rheumatoid arthritis susceptibility. Tsitol Genet 48(3):24–29

    CAS  PubMed  Google Scholar 

  160. Maldonado-Montoro M, Canadas-Garre M, Gonzalez-Utrilla A et al (2018) Influence of IL6R gene polymorphisms in the effectiveness to treatment with tocilizumab in rheumatoid arthritis. Pharmacogenomics J 18(1):167–172

    Article  CAS  PubMed  Google Scholar 

  161. Ranganathan P, McLeod H (2006) Methotrexate pharmacogenetics: first step toward individualized therapy in rheumatoid arthritis. Arthritis and Rheumatism 54(5):1366–1377

    Article  CAS  PubMed  Google Scholar 

  162. Ranganathan P (2005) Pharmacogenomics of tumor necrosis factor antagonists in rheumatoid arthritis. Pharmacogenomics 2(4):279–282

    Google Scholar 

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  1. Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA

    Atinuke Aluko & Prabha Ranganathan

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  1. Atinuke Aluko
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  2. Prabha Ranganathan
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Correspondence to Prabha Ranganathan .

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  1. PharmTao, Santa Clara, CA, USA

    Qing Yan

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Aluko, A., Ranganathan, P. (2022). Pharmacogenetics of Drug Therapies in Rheumatoid Arthritis. In: Yan, Q. (eds) Pharmacogenomics in Drug Discovery and Development. Methods in Molecular Biology, vol 2547. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-2573-6_19

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  • DOI: https://doi.org/10.1007/978-1-0716-2573-6_19

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